This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Multiple vaccine strategies to induce protective immunity against HIV infection and prevention of progression to AIDS, have been unsuccessful as of to date. The current thinking is to look for " outside the box" approaches to overcome this bottle neck in developing an effective vaccine. We hypothesize that one such approach is to investigate the role of an envelope protein derived from an unrelated virus (GBV-C) as an immunogen that will induce broadly cross-reactive high titered neutralizing antibodies that will prevent infection in immunized rhesus monkeys following challenge with a SHIV isolate. GBV-C is prevalent in nearly 1% of blood donors in the US but is not associated with any diseases. Several studies have shown that exposure to GBV-C and HIV is associated with higher CD4+ T cell numbers, lower infection and prolonged survival times when compared with HIV infection alone. Those events appear to correlate with the development of antibodies to envelope protein of GBV-C and raise the possibility that such antibodies may modify HIV infection and disease progression. Recent studies have demonstrated that polyclonal or monoclonal antibodies to the envelope protein neutralized a broad panel of HIV isolates and a SHIV isolate in vitro. Therefore, we propose to conduct a proof -of -concept pilot study using rhesus monkeys that will be vaccinated with DNA coding for the envelope protein followed by booster doses of the envelope protein. The immunized monkeys will be monitored for the development of immune responses to the envelope protein and along with unvaccinated control monkeys will be challenged with a SHIV isolate to determine the outcome. It is anticipated that this strategy will provide important information toward the development of an effective vaccine for the prevention of HIV infection and or disease progression in humans.